Program in Neuroscience, University of Maryland, Baltimore, Baltimore, MD, United States

Departments of Pharmacology and Physiology, University of Maryland, Baltimore, Baltimore, Maryland, United States

The mechanisms underlying the establishment of sex
differences in the developing brain are still largely unknown, but recent
evidence suggests an increasing role for non-neuronal cells in this process. Microglia aid in synaptic pruning,
tissue homeostasis, and regulate neuronal precursor populations through
signaling and targeted phagocytosis of viable cells- termed “phagoptosis”. To
further support this, we implicated microglia as an integral component of brain
sexual differentiation in the preoptic area1, suggesting an important
signaling capacity of these cells in organizing sex-specific brain structure
and behavior. Additionally, we reported
a sex difference in cell proliferation in the developing rat medial amygdala
(MeA) that was mediated by endocannabinoids, with females having higher cell
proliferation rates than males. These differences in cell proliferation
correlated to behavioral changes, as female treatment with the CB1/2 agonist
WIN55,212-2 masculinized juvenile social play behavior2.
Further investigation revealed a surprising new role for microglia in mediating
the number of newborn cells with effects specific to the postnatal
MeA. Males displayed twice as many Iba1+ microglia exhibiting a
phagocytic morphology as compared to females. These microglia contained
one or more processes that ended in a phagocytic cup, but otherwise exhibited
thick or ramified processes. Furthermore, exogenous CB1 receptor agonist
treatment increased the number of phagocytic microglia in females to levels
observed in males. Treatment with the tetracycline derivative
minocycline, an inhibitor of microglial activation, increased male BrdU+ cell
counts to female levels, but did not alter the number of female BrdU+
cells. We found every microglia exhibiting a phagocytic morphology was
also DAPI+, a marker for DNA, within the phagocytic cup; thus, we sought to
characterize the specific cell types targeted by the microglia. BrdU
colocalized to the phagocytic cup, in addition to inhibitory interneuron
markers calbindin and nNos. This work was supported by RO1 MH52716-018 to
MMM.